Sickle cell anemia is an inherited disorder of erythrocytes characterized by chronic anemia, recurrent pain, susceptibility to infections, chronic and recurrent organ dysfunction, and diminished life-expectancy. Even among patients having documented homozygous sickle cell anemia (Hb SS) exists an astonishing degree of variability in clinical severity. Some die from strokes as young children, others live well into their seventies. Some seek medical attention for pain weekly, others go years without pain. The absolute nature of current therapeutic measures for sickle cell disease (SCD), eg termination of pregnancy and bone marrow transplantation (BMT), emphasizes the importance of pretherapeutic predictions of mild and severe disease before the nature of the disease has been declared. In this regard, we propose to use polymerase chain reaction (PCR)-based methods to detect sequence variations that are related to disease severity - alpha-globin genotypes, beta-cluster restriction fragment length polymorphism (RFLP) haplotypes, binding sites for erythroid-specific trans-acting transcription elements, and beta-cluster locus control region (LCR) sequences. PCR-based methods for detecting these sequences will provide the basis for developing a diagnostic kit that will predict whether SCD will be mild or severe, and will guide decisions regarding termination of pregnancy and undertaking BMT.